TW201033181A - Purification of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine - Google Patents

Abstract

The present invention concerns a process for the manufacture of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine.

Description

201033181 六、發明說明： 【發明所屬之技術領域】 本發明係關於1-[2-(2,4-二甲苯硫基）苯基]哌啡之製造 及純化。 【先前技術】 以WO 03/029232及WO 20〇7/144〇05公開之國際專利 申請案揭示化合物1_[2_(2,4_二曱苯硫基）_苯基]哌畊及其鹽 對企清素轉運體及血清素受體3及ΙΑ (5-HT3及5_ht ) 具有親和力。此藥理學特徵使得使用該等化合物治療諸如 抑鬱症及焦慮症之情緒異常症具有吸引力。實際上，當前 正對該化合物治療情緒異常症進行臨床試驗。 藥品製造為具有很多有關活性醫藥成份（API)之品質 /純度之準則及規則的高度管制領域。因此要求製造途徑確 保最終產物之高純度，一種達成此目標之方法為研發特定 純化步驟。 結晶及再結晶為提供經純化化合物之熟知方法。w〇 2007/144005中所提供之實施例揭示二曱苯硫基）_ 苯基]哌畊及其鹽可自諸如乙酸乙酯、乙酸乙酯/水、水及甲 苯之溶劑中結晶。 【發明内容】 本發明人已發現，在1-[2-(2,4-二甲苯硫基）_苯基;|哌畊 及其醫樂學上可接受之鹽之合成中包括一個步驟（在該步 驟中由卜[2-(2,4-二曱苯硫基）-苯基]痕口井_HBr製備 1-[2-(2,4-二曱苯硫基）-苯基]哌畊_HBr異丙醇溶劑合物）可 3 201033181 移除或減少雜質且從而提供經純化之丨_r _ ί^ΊΖ’4·二甲苯硫 基）-苯基]旅畊及其醫藥學上可接受之鹽，例如心形式之 鹽。 因此，在一具體實例中，本發明提供一種製造1[2_(2 4 二曱苯硫基）苯基]哌畊或其醫藥學上可接受之鹽的方法，’气 方法包括藉由將1-[2-(2,4-二曱苯硫基）苯基]哌畊汨以鹽= 解於包含超過65% (ν/ν)之異丙醇之溶劑中獲得溶液:: 驟。 ’ 在一具體實例中，本發明提供一種製造卜口-^〆-二甲 苯硫基）苯基]哌畊或其醫藥學上可接受之鹽的方法，該方法 包括使1 -[2-(2,4-二甲苯硫基）苯基]哌畊-HBr異丙醇溶劑合 物自包含超過65% ( Wv)之異丙醇之溶劑中沈澱之步驟。 在一具體實例中，本發明係關於一種製造— 甲苯硫基）苯基]哌畊或其醫藥學上可接受之鹽之方法，該方 法包括將1-[2-(2,4-二甲苯硫基）苯基]哌畊_HBr異丙醇溶劑 合物溶解於不與該化合物形成穩定溶劑合物之溶劑中的步 驟。 在一具體實例中，本發明提供一種為二甲笨 硫基）苯基]哌畊_HBr異丙醇溶劑合物之化合物。 【實施方式】 本發明係關於一種可用於製造^[2-(2,4-二甲苯硫基） 苯基]哌畊及其醫藥學上可接受之鹽的純化步驟。以下描繪 1 _[2·(2,4-二甲笨硫基）苯基]0辰啡之分子結構 201033181201033181 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to the production and purification of 1-[2-(2,4-dimethylphenyl)phenyl]pipepone. [Prior Art] The international patent application published in WO 03/029232 and WO 20 〇 7/144 〇 05 discloses compound 1_[2_(2,4-diphenylthio)phenyl] piperidine and its salt pair The phytochemical transporter and serotonin receptors 3 and ΙΑ (5-HT3 and 5_ht) have affinity. This pharmacological profile makes the use of such compounds attractive for the treatment of mood disorders such as depression and anxiety. In fact, clinical trials of the compound for the treatment of mood disorders are currently underway. Pharmaceutical manufacturing is a highly regulated area with many guidelines and rules regarding the quality/purity of active pharmaceutical ingredients (APIs). Therefore, the manufacturing route is required to ensure the high purity of the final product. One way to achieve this goal is to develop a specific purification step. Crystallization and recrystallization are well known methods for providing purified compounds. The examples provided in WO 2007/144005 disclose that diphenylthiophenyl)-phenyl] piperazine and its salts can be crystallized from solvents such as ethyl acetate, ethyl acetate/water, water and toluene. SUMMARY OF THE INVENTION The present inventors have discovered that a step is included in the synthesis of 1-[2-(2,4-dimethylphenyl)-phenyl;|piped and its pharmaceutically acceptable salt ( In this step, 1-[2-(2,4-diphenylthio)-phenyl] is prepared from [2-(2,4-diphenylthio)-phenyl] trace well_HBr] Piper _HBr isopropanol solvate) 3 201033181 Remove or reduce impurities and thereby provide purified 丨 _r _ ί ^ ΊΖ '4 · xylylthio) - phenyl] travel and its medicine An acceptable salt, such as a salt in the form of a heart. Accordingly, in one embodiment, the present invention provides a method of producing 1[2_(2 4 dimethylphenylthio)phenyl]piperone or a pharmaceutically acceptable salt thereof, the 'gas method comprising -[2-(2,4-Diphenylsulfanyl)phenyl]pyrazine is obtained as a solution by salt = solution in a solvent containing more than 65% (v/v) of isopropanol:: In one embodiment, the present invention provides a method of producing a sulphate-dimethylthiophenyl) piperidine or a pharmaceutically acceptable salt thereof, the method comprising the step of 1 -[2-( The step of precipitating the 2,4-dimethylthio)phenyl]pitricon-HBr isopropanol solvate from a solvent comprising more than 65% (wv) of isopropanol. In one embodiment, the invention relates to a process for the manufacture of -toluthio)phenyl]piperone or a pharmaceutically acceptable salt thereof, which comprises 1-[2-(2,4-xylene) The thio)phenyl]piperidine-HBr isopropanol solvate is dissolved in a solvent which does not form a stable solvate with the compound. In one embodiment, the invention provides a compound which is a solvate of dimethyl thiophenyl) phenyl] piperazine_HBr isopropanol. [Embodiment] The present invention relates to a purification step which can be used for the production of [2-(2,4-dimethylphenylthio)phenyl] piperazine and a pharmaceutically acceptable salt thereof. The molecular structure of 1 _[2·(2,4-dimethylphenyl)phenyl]0 morphine is depicted below.

詳言之，醫藥學上可接受之鹽為無毒酸之酸加成鹽。 該等鹽包括由有機酸（諸如順丁烯二酸、反丁烯二酸、苯 甲酸、抗壞血酸、琥珀酸、草酸、雙亞甲基柳酸、甲磺酸、 〇 乙一磧酸、乙酸、丙酸、酒石酸、柳酸、檸檬酸、葡萄糖 酸、乳酸、蘋果酸、杏仁酸、肉桂酸、甲基順丁烯二酸、 天冬胺酸、硬脂酸、棕橺酸、衣康酸（itaconic acid)、乙 醇酸、對胺基苯甲酸、麩胺酸、苯磺酸、茶鹼乙酸以及8_ 鹵茶鹼（例如8-溴茶鹼））形成之鹽。該等鹽亦可由無機 鹽（諸如氫氣酸、氫溴酸、硫酸、胺基磺酸、磷酸及硝酸） 形成。尤其提及由乳酸、甲磺酸、順丁烯二酸、反丁烯二 酸、内消旋酒石酸、（+)-酒石酸、（·）_酒石酸、氯氯酸、氮 ©溴’酸、硫酸、填酸及硝酸形成之鹽。特別提及氮漢酸鹽。 如WO 2007/144005中所顯示，Wy(2,4_二甲苯硫基） 笨基]哌畊之HBr鹽晶體呈多晶型且以（至少）三種不同形 式存在，亦即α -、沒_及r _形式（、以…及 ga^na-form )。依據Dsc及溶解度數據判斷1 _形式為最 穩定形式，且其可由位於約6 86、9 73 …之獅反射加以特性化+形式之XRpD圖案示(於 圖1中。請參見製備Θ·形式之^(^二曱苯硫基）苯基] 哌畊-HBr之實施例1。 5 201033181 該化合物之製造方法揭示於WO 03/029232及 WO 2007/144005中。一種製造方法係利用可製備N-芳基鍵的 Buchwald紅催化法（參見US 5,576,460 )。在此方法中， 在高pH下將2,4-二甲基硫酚、2-溴-1-碘苯及哌畊與鈀源及 膦配位體於例如甲苯之適合溶劑中一起混合。可使用其他 二鹵苯且可保護旅π井。適合把源包括Pd2dba3、Pddba:及 Pd(OAc)2。dba為二亞苄基丙酮之縮寫。尤其提及Pddba2。 適合膦配位體包括單牙及雙牙配位體，諸如外消旋2,2，-雙-二苯基磷烷基_[1，1’]聯萘（rac-BINAP) 、1，1’-雙（二苯基膦 〇 基）二茂鐵（DPPF)、雙-(2-二笨基膦基苯基）醚（DPEphos)、 三-第三丁基膦（Fu氏鹽）、聯苯-2-基-二-第三丁基-膦、 聯苯-2-基-二環己基-膦、（2’-二環己基磷烷基-聯苯-2-基）-二曱基-胺、[2’-(二-第三丁基-磷烷基）-聯苯-2-基]-二甲基-胺及一壞己基_(2',4^6,-二丙基-聯苯-2-基）-填烧。此外，可 使用諸如氯化1，3-雙-(2,6-二-異丙基-苯基）-311-咪唑-1-鏽之 碳烯配位體替代膦配位體。詳言之，rac_BINAP為適用配位 體。添加鹼至反應混合物中可增大或提高pH。詳言之，可 ® 使用選自NaO(t-Bu)、KO(t-Bu)及Cs2C03之鹼。亦可應用 諸如1，8-二氮雜雙環[5.4.0]十一-7-烯（〇611)及1，4-二氮雜 一環[2.2_2]辛烧（DABCO )之有機驗。尤其提及NaO(t-Bu) 及 KO(t-Bu)。 或者’可在第一步驟中使硫酚及二鹵苯反應以獲得苯 硫基苯基，可將其分離’之後與β底讲或經保護之n底啡進一 步反應以獲得所要產物。 6 201033181 為獲得l-[2-(2,4-二甲苯硫基）苯基]哌畊之所要鹽，可 使以上方法中所獲得之相應自由鹼與適當酸反應以使鹽沈 殿。詳言之，可使用氫溴酸水溶液使4-二甲苯硫基） 苯基]派讲-HBr沈殿。 本發明提供一種可在例如製造途徑之此步驟使用的純 化方法。該方法提供一種經高度純化之終產物，且此外， 該方法允許使用低純度起始物質。總之，將HBr鹽溶解於 包含異丙醇之溶液中，使相應異丙醇溶劑合物自該溶液中 ® 沈澱。據本發明者之經驗，若溶液包含超過65% ( v/v )之 異丙醇，則形成異丙醇溶劑合物。可藉由冷卻產生沈澱。 隨後將異丙醇溶劑合物溶解於不形成溶劑合物之溶劑中， 且可例如藉由蒸餾移除或減少異丙醇及/或水。移除或減少 異丙醇可用以增加產率。最後使二曱苯硫基）苯基] 哌畊-HBr沈澱。可選用用於沈澱之溶劑及條件（例如溫度 變化率、晶體接種）控制所得晶體形式，術語「不形成溶 〇 劑合物之溶劑」意指不參與形成二曱苯硫基）苯基] 哌畊-HBr鹽之穩定溶劑合物的溶劑。實例包括水、thf(四 乳吱味）、二甲苯、苯、甲醇、乙醇、丙嗣及甲苯及其混 合物。尤其提及甲苯與水之混合。尤其提及水中包含超過 80%之甲苯之混合物。 藉由使相應溶劑合物沈澱來純化並不常見，且如 Hilfiker，R.(編者）.P〇Iym〇rphism in 加 刪⑽㈤ W赠y. WUey-VCH，2_.(第12·π頁）中所論述，一般僅 田待’、屯化之產物難以呈無溶劑形式結晶時，推薦該純化步 7 201033181In particular, the pharmaceutically acceptable salt is a non-toxic acid addition salt. Such salts include organic acids (such as maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylene salicylic acid, methanesulfonic acid, phthalic acid, acetic acid, C Acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, methyl maleic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid (itaconic) Salt formed from acid), glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, theophylline acetic acid, and 8-halophylline (eg, 8-bromophylline). These salts may also be formed from inorganic salts such as hydrogen acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid and nitric acid. Mention is made in particular of lactic acid, methanesulfonic acid, maleic acid, fumaric acid, meso-tartaric acid, (+)-tartaric acid, (·)_tartaric acid, chloric acid, nitrogen, bromine-acid, sulfuric acid , salt filled with acid and nitric acid. Particular mention is made of the nitrogen hanate. As shown in WO 2007/144005, Wy (2,4-dimethylthio) stupyl] HBr salt crystals are polymorphic and exist in (at least) three different forms, namely α -, no _ And r _ form (, with ... and ga^na-form). The 1 _ form is judged to be the most stable form based on the Dsc and solubility data, and it can be represented by the XRpD pattern of the characterization + form of the lion reflection at about 6 86, 9 73 ... (see Figure 1 for a preparation). Example 1 of ^(^ diphenylsulfenyl)phenyl]piped-HBr. 5 201033181 The process for the production of this compound is disclosed in WO 03/029232 and WO 2007/144005. One manufacturing method utilizes N- Buchwald red catalysis of aryl bonds (see US 5,576,460). In this process, 2,4-dimethylthiophenol, 2-bromo-1-iodobenzene and piperene with palladium source and phosphine at high pH The ligands are mixed together in a suitable solvent such as toluene. Other dihalobenzenes can be used and the Zn well can be protected. Suitable sources include Pd2dba3, Pddba: and Pd(OAc)2. dba is an abbreviation for dibenzylideneacetone. In particular, Pddba2 is mentioned. Suitable phosphine ligands include monodentate and bidentate ligands such as racemic 2,2,-bis-diphenylphosphinoalkyl-[1,1']binaphthalene (rac- BINAP), 1,1'-bis(diphenylphosphinodecyl)ferrocene (DPPF), bis-(2-diphenylphosphinophenyl)ether (DPEphos), tri-tert-butylphosphine ( Fu ), biphenyl-2-yl-di-tert-butyl-phosphine, biphenyl-2-yl-dicyclohexyl-phosphine, (2'-dicyclohexylphosphinoalkyl-biphenyl-2-yl)- Dimercapto-amine, [2'-(di-tert-butyl-phosphinoalkyl)-biphenyl-2-yl]-dimethyl-amine and a bad hexyl group (2', 4^6,- Dipropyl-biphenyl-2-yl)-filled. In addition, 1,3-bis-(2,6-di-isopropyl-phenyl)-311-imidazole-1-rust such as chlorinated chloride can be used. The carbene ligand replaces the phosphine ligand. In particular, rac_BINAP is a suitable ligand. Adding a base to the reaction mixture increases or increases the pH. In particular, the ® can be selected from NaO (t-Bu) ), a base of KO(t-Bu) and Cs2C03, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (〇611) and 1,4-diaza-acyclic ring may also be used [ 2.2_2] Organic test of DABCO. Especially mentions NaO(t-Bu) and KO(t-Bu). Or 'can be used in the first step to react thiophenol and dihalobenzene to obtain phenylthio The phenyl group, which can be isolated, is further reacted with a beta-based or protected n-parcine to obtain the desired product. 6 201033181 To obtain 1-[2-(2,4-dimethylphenyl)phenyl]piperidin If you want to use the salt, you can make it above. The corresponding free base obtained in the method is reacted with an appropriate acid to cause the salt to sink. In particular, an aqueous solution of hydrobromic acid can be used to make 4-dimethylthio)phenyl]-HBr. The present invention provides a purification process that can be used, for example, in this step of the manufacturing route. This process provides a highly purified end product and, in addition, the process allows the use of low purity starting materials. In summary, the HBr salt is dissolved in a solution containing isopropanol to precipitate the corresponding isopropanol solvate from the solution. According to the experience of the inventors, if the solution contains more than 65% (v/v) of isopropanol, an isopropanol solvate is formed. Precipitation can be produced by cooling. The isopropanol solvate is then dissolved in a solvent that does not form a solvate, and the isopropanol and/or water can be removed or reduced, for example, by distillation. Removal or reduction of isopropanol can be used to increase the yield. Finally, diphenylsulfonyl)phenyl]piperidine-HBr was precipitated. The obtained crystal form can be controlled by using a solvent and conditions for precipitation (for example, temperature change rate, crystal inoculation), and the term "solvent which does not form a solvate composition" means not participating in the formation of diphenylthiophenyl) phenyl] piperidine A solvent for the stable solvate of the cultivating-HBr salt. Examples include water, thf (tetramilin), xylene, benzene, methanol, ethanol, propionium and toluene, and mixtures thereof. Particular mention is made of the mixing of toluene and water. Particular mention is made of mixtures containing more than 80% toluene in water. Purification by precipitation of the corresponding solvate is not common, and is as in Hilfiker, R. (editor). P〇Iym〇rphism in addition and deletion (10) (v) W gift y. WUey-VCH, 2_. (page 12·π) As discussed in the above, it is generally only when the product is not ready, and the product of sputum is difficult to crystallize in the form of no solvent. This purification step 7 is recommended.

右所要鹽不同於HBr鹽，則可依其他方法使用經純化 HBr鹽作為起始物質，其中冑HBr鹽溶解視情況獲得自 由鹼形式且藉由適當酸沈澱來獲得所要鹽。 在一具體實例中，本發明提供一種製造Μ2-(2,4·二曱 笨硫基）苯基]哌畊或其醫藥學上可接受之鹽之方法，該方法 包括藉由在諸如回流溫度之高溫下將二甲苯硫基） 苯基]哌畊-HBr鹽溶解於包含超過65% (v/v)之異丙醇之 /令劑中獲得溶液之步驟。或者，不升高溫度，而此會延長 處理時間。詳言之’該醫藥學上可接受之鹽為冷-形式之 鹽。在一具體實例中，該溶劑包含超過85% ( v/v )之異丙 醇。 在一具體實例中，本發明提供一種製造二甲 苯硫基）苯基]哌畊或其醫藥學上可接受之鹽之方法，該方法 包括例如藉由冷卻而使二曱苯硫基）笨基]哌畊 •HBr異丙醇溶劑合物自包含超過65% ( v/v)之異丙醇之溶 劑中沈澱之步驟。詳言之，該醫藥學上可接受之鹽為卢_形 式之HBr鹽。在一具體實例中，該溶劑包含超過85% ( v/v ) 之異丙醇。 在一具體實例中，本發明提供一種製造卜[2-(2,4-二曱 苯硫基）笨基]哌畊或其醫藥學上可接受之鹽之方法，該方法 包括將1-[2-(2,4-二甲苯硫基）苯基]哌畊_HBr異丙醇溶劑合 物/合解於不形成溶劑合物之溶劑中、隨後使二曱 笨硫基）苯基]哌畊-HBr沈澱之步驟。詳言之，該醫藥學上 201033181 可接受之鹽為HBr鹽，諸如冷-形式。 在一具體實例中，本發明提供一種製造二甲 苯硫基）苯基]哌畊或其醫藥學上可接受之鹽、尤其形式 之HBr鹽的方法，該方法包括以下步驟·· a )藉由例如在高溫（諸如回流溫度）下將丨_[2·(2,4_ 二曱苯硫基）苯基]哌畊-HBr溶解於包含超過65%( ν/ν)(諸 如超過85% ( v/v ))之異丙醇的溶劑中來獲得溶液； b) 例如藉由冷卻使^[2-(2,4-二甲苯硫基）苯基]哌畊 -HBr異丙醇溶劑合物自該所得溶液中沈澱； c) 將1-[2-(2,4-二甲苯硫基）苯基]哌畊_HBr異丙醇溶劑 合物溶解於不形成溶劑合物之溶劑中；詳言之，該不形成 溶劑合物之溶劑包含超過80% (諸如超過90% )之甲苯； 及 d) 例如藉由冷卻使二甲苯硫基）苯基]哌畊 -HBr自c )所得之溶液中沈澱； 若a)所用之HBr鹽含有大量雜質，則宜將b)所得之 異丙Sf· ί·今劑&物再〉谷解於包含超過6 5 %異丙醇之溶劑中， 隨後如b)中所述進行沈澱。 在一具體實例中’本發明係關於一種藉由上述方法之 一直接獲得之產物。 在一具體實例中’本發明係關於一種自固體丨_[2_(2,4_ 二甲苯硫基）苯基]哌畊-HBr鹽或卜[2-(2,4-二曱苯硫基）苯 基]哌畊-HBr之溶液中移除或減少雜質的方法，該方法包括 以下步驟： 9 201033181 a )視情況將包含超過65%( v/v )(諸如超過85%( v/v )) 之異丙醇的溶劑與固體卜[2-(2,4-二曱苯硫基）苯基]旅0井 -HBr或1_[2-(2,4_二曱苯硫基）苯基]哌畊HBr之溶液混合， 適當時例如隨後加熱，獲得1 _[2-(2,4-二曱苯硫基）苯基]11 底 畊-HBr之溶液； b )冷卻該所得溶液以使卜[2-(2，4-二曱苯硫基）苯基]t»辰 時-HBr異丙醇溶劑合物沈澱； c) 將1-[2-(2,4-二曱苯硫基）苯基]β底讲- HBr異丙醇溶劑 合物溶解於不形成溶劑合物之溶劑中；及 d) 例如藉由冷卻使^[2-(2,4-二甲苯硫基）苯基]哌畊 -HBr自c )所得之溶液中沈澱； 詳言之’ c )所用之不形成溶劑合物之溶劑係選自水、 THF、二甲苯、苯、曱醇、乙醇、丙酮及曱苯及其混合物。 尤其提及曱苯與水之混合，尤其包含超過8〇% ( v/v )(諸 如超過90%(v/v))之甲苯。 該等雜質之實例包括鈀（Pd) 、ΐ·[2-(2,4-二甲基-笨硫 基）-苯基]-4-(2-哌畊_1_基-苯基）_哌畊（化合物丨）、1[2_仏 氣-2,4-二甲基-苯硫基）苯基]哌畊（化合物2)、 二甲苯硫基）苯基]哌畊（化合物3)及卜[2_(2,4_二甲苯硫基） 笨基]哌畊-HBr第三丁醇溶劑合物，亦參見圖4_6。鈀為使 用Pd催化劑所產生之雜質。「Pd」或「鈀」欲指所有含有 之化合物。化合物里為在兩個哌畊氮處經催化而形成 N-芳基鍵時所產生之雜質。化合物2及3為可能被相應^ 氣或2,5-二甲基化合物污染< 2,二甲基硫酚原材料所攜 201033181 帶之雜質。由於反應中使用第三丁醇鈉，因此會形成第三 丁醇溶劑合物。 一 為進一步說明本發明，以下描述可能有幫助。將 1-[2-(2,4-二曱苯硫基）苯基]哌畊-HBr ( A)饋入反應器中'。 添加異丙醇（l〇-15L/kgA)及水（〇3_1〇L/kgA)且開始 攪拌。加熱混合物至回流且溶解所有^(2,4·二曱苯硫基）苯 基]哌畊ΗΒγ鹽。使溶液冷卻至<2〇t，且過濾晶體（異丙 醇溶劑合物）且用異丙醇（總共2.4_2.6L/kgA)洗滌兩次。 將濕濾餅再饋入反應器中且添加曱苯（4-6 L/kg A )。將濕 濾餅中之異丙醇/水共沸餾出且隨同水（〇2 〇·3χΑ) 一起添 加蒸餾中所損耗之曱苯。加熱混合物至回流且溶解所有 1-(2,4-二曱苯硫基）苯基]哌畊_HBr。使溶液冷卻至<2〇°c , 且過濾晶體且用甲苯（總共丨.0-4.0 L/kg A)洗滌兩次。使 晶體在例如60。(：之高溫及真空下脫水。獲得冷-形式之 ^2,4-二曱苯硫基）苯基]略啡-HBr。 如實施例5所顯示，本發明之純化方法優於等效再結 晶方法之處在於可減少或移除更多雜質。因此，本發明之 純化方法具有獨特且不可預見之品質。 如上所說明，1-(2,4-二曱苯硫基）苯基]哌畊-HBr異丙 醇溶劑合物適用於純化二甲苯硫基）苯基]哌畊及其 醫藥學上可接受之鹽之方法步驟。 因此’在一具體實例中，本發明係關於一種包含1-(2,4- 一甲笨硫基）苯基]哌畊於超過65% (v/v)之異丙醇中之液 體溶液。 11 201033181 在一具體實例中，本發明係關於1-(2,4-二甲苯硫基）苯 基]哌畊-HBr異丙醇溶劑合物。 在一具體實例中，本發明係關於具有位於約6.44、 8.13 ' 8.77、10.41 ( °2㈠之XRPD反射（例如具有如圖2 所示之XRPD圖案）之W2,4-二甲苯硫基）苯基]哌畊-HBr 異丙醇溶劑合物。 應庄思使用1-(2,4-一曱苯硫基）苯基]0辰啡_jjBr異丙醇Where the desired salt is different from the HBr salt, the purified HBr salt can be used as a starting material by other methods, wherein the hydrazine HBr salt is dissolved as appropriate to obtain a free base form and the desired salt is obtained by appropriate acid precipitation. In one embodiment, the present invention provides a method of producing Μ2-(2,4·dioxathio)phenyl]piperone or a pharmaceutically acceptable salt thereof, the method comprising The step of dissolving the xylylthio)phenyl]piperidine-HBr salt in a solution containing more than 65% (v/v) of isopropanol at a high temperature to obtain a solution. Or, do not raise the temperature, which will increase the processing time. In particular, the pharmaceutically acceptable salt is a cold-form salt. In one embodiment, the solvent comprises more than 85% (v/v) isopropanol. In one embodiment, the present invention provides a process for the manufacture of xylthio)phenyl]piperone or a pharmaceutically acceptable salt thereof, which process comprises, for example, cooling to a diphenylthio group. The step of precipitation of the piperidine•HBr isopropanol solvate from a solvent comprising more than 65% (v/v) isopropanol. In particular, the pharmaceutically acceptable salt is the HBr salt of the form of ruthenium. In one embodiment, the solvent comprises more than 85% (v/v) isopropanol. In one embodiment, the invention provides a method of making a [2-(2,4-diphenylthio)phenyl] or a pharmaceutically acceptable salt thereof, the method comprising 1-[ 2-(2,4-Dimethylthio)phenyl]piperidine-HBr isopropanol solvate/dissolved in a solvent which does not form a solvate, followed by a dithiol phenyl] phenyl] piperidine The step of ploughing-HBr precipitation. In particular, the pharmaceutically acceptable salt of 201033181 is an HBr salt, such as a cold-form. In one embodiment, the present invention provides a process for the manufacture of xylthio)phenyl] piperazine or a pharmaceutically acceptable salt thereof, especially a form of HBr salt, the process comprising the steps of: a) For example, at a high temperature (such as reflux temperature), 丨_[2·4_diphenylsulfenyl)phenyl]pitricin-HBr is dissolved in more than 65% (v/v) (such as more than 85% (v) /v)) a solution of isopropanol to obtain a solution; b) for example, by cooling, [[2-(2,4-dimethylthio)phenyl]piped-HBr isopropanol solvate Precipitating in the resulting solution; c) dissolving 1-[2-(2,4-dimethylphenyl)phenyl]piperidine-HBr isopropanol solvate in a solvent which does not form a solvate; The solvent which does not form a solvate comprises more than 80% (such as more than 90%) of toluene; and d) in a solution obtained by cooling, for example, xylthio)phenyl]piperidine-HBr from c) Precipitation; if the HBr salt used in a) contains a large amount of impurities, the isopropyl Sf· ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ Precipitation as described in b)In one embodiment, the invention relates to a product obtained directly by one of the above methods. In a specific example, the present invention relates to a self-solid 丨[[2_(2,4-dimethylthio)phenyl]piped-HBr salt or a [2-(2,4-diphenylenethio) group. A method of removing or reducing impurities in a solution of phenyl]piperon-HBr, the method comprising the steps of: 9 201033181 a) optionally comprising more than 65% (v/v) (such as more than 85% (v/v)) The solvent of isopropanol and the solid [2-(2,4-diphenylthio)phenyl] brigade 0-HBr or 1_[2-(2,4-diphenylthio)phenyl a solution of piperene HBr mixed, if appropriate, for example, followed by heating to obtain a solution of 1 _[2-(2,4-diphenylthio)phenyl]11 bottom argon-HBr; b) cooling the resulting solution to [2-(2,4-Diphenylthio)phenyl]t»--HBr isopropanol solvate precipitation; c) 1-[2-(2,4-diphenylthio) Phenyl]β bottom - HBr isopropanol solvate is dissolved in a solvent which does not form a solvate; and d) ^[2-(2,4-dimethylthio)phenyl] is cooled, for example, by cooling] Piper-HBr precipitates from the solution obtained from c); in detail, the solvent used to form the solvate used in 'c) is selected from the group consisting of water, THF, xylene, benzene, decyl alcohol, and B. Alcohol, acetone and terpene and mixtures thereof. Particular mention is made of a mixture of terpene and water, especially comprising more than 8% (v/v) (e.g. more than 90% (v/v)) of toluene. Examples of such impurities include palladium (Pd), ΐ·[2-(2,4-dimethyl-phenylthio)-phenyl]-4-(2-piperidin-1-yl-phenyl)_ Piper (Compound 丨), 1[2_仏-2,4-Dimethyl-phenylthio)phenyl]Plough (Compound 2), Xylylene)phenyl] Pipeline (Compound 3) And [2_(2,4-dimethylthio) stupid] piperazine-HBr tert-butanol solvate, see also Figure 4-6. Palladium is an impurity produced by using a Pd catalyst. "Pd" or "palladium" is intended to mean all compounds contained therein. The compound is an impurity produced when catalyzed by two piperazines to form an N-aryl bond. Compounds 2 and 3 are impurities which may be contaminated by the corresponding gas or 2,5-dimethyl compound < 2, dimethyl thiophenol raw material carrying 201033181. Since the sodium third butoxide is used in the reaction, a third butanol solvate is formed. In order to further illustrate the invention, the following description may be helpful. 1-[2-(2,4-Diphenylthio)phenyl]pitricin-HBr (A) was fed into the reactor. Isopropanol (l〇-15L/kgA) and water (〇3_1〇L/kgA) were added and stirring was started. The mixture was heated to reflux and all of the ^(2,4·diphenylthio)phenyl]piperidinium gamma salt was dissolved. The solution was cooled to < 2 Torr, and the crystals (isopropanol solvate) were filtered and washed twice with isopropyl alcohol (2.4-2.6 L/kg A total). The wet cake was fed back into the reactor and toluene (4-6 L/kg A) was added. The isopropanol/water in the wet cake was azeotropically distilled and the toluene lost in the distillation was added along with water (〇2 〇·3χΑ). The mixture was heated to reflux and all 1-(2,4-diphenylthio)phenyl]pitricin-HBr was dissolved. The solution was cooled to < 2 ° C, and the crystals were filtered and washed twice with toluene (total 丨.0-4.0 L/kg A). Let the crystal be at, for example, 60. (: Dehydration at high temperature and under vacuum. Cold-form of ^2,4-diphenylthio)phenyl]succinyl-HBr was obtained. As shown in Example 5, the purification method of the present invention is superior to the equivalent recrystallization method in that more impurities can be reduced or removed. Therefore, the purification method of the present invention has a unique and unpredictable quality. As indicated above, 1-(2,4-diphenylthio)phenyl]pitricin-HBr isopropanol solvate is suitable for the purification of xylylthio)phenyl]piperone and its pharmaceutically acceptable Method steps for the salt. Thus, in one embodiment, the invention relates to a liquid solution comprising 1-(2,4-monophenylthio)phenyl]piped in more than 65% (v/v) isopropanol. 11 201033181 In one embodiment, the invention relates to 1-(2,4-dimethylphenyl)phenyl]piped-HBr isopropanol solvate. In one embodiment, the invention relates to W2,4-dimethylthio)phenyl having XRPD reflections (e.g., having an XRPD pattern as shown in Figure 2) at about 6.44, 8.13 ' 8.77, 10.41 (° 2 (one)) ] Pipeline-HBr isopropanol solvate. Ying Zhuangsi uses 1-(2,4-monophenylthio)phenyl]0 morphine _jjBr isopropanol

溶劑合物之另一益處與其處理特性有關。溶劑合物不穩定 且易用過濾器處理。 本文所引用之所有參考文獻均以全文引用的方式併入 本文中，且該引用的程度就如同已個別地及特定地指示將 各參考文獻以全文引用的方式併入且陳述於本文中一俨 (達法律所允許之最大程度），不論本文中別處單別提= 之任何特定文獻之併入。 π ,入％糊低蜩，古則描述本 之上下文中所用之術語「-（a、」及「該（the)Another benefit of solvates is related to their handling characteristics. The solvate is unstable and easy to handle with a filter. All references cited herein are hereby incorporated by reference in their entirety to the extent of the extent of the disclosure of the disclosure of the entire disclosure (to the maximum extent permitted by law), regardless of the incorporation of any particular document elsewhere in this document. π, into the low paste, the ancient description of the term used in the context of "- (a," and "the (the)

類似如不物視為涵蓋單數與複數。舉例而言，除非另 明，否則應瞭解「玆仆人私,a 笏化。物（the Compound)」一詞係 發月或特定描述之態樣的各種化合物。 ^另外指明，否則本文所提供之所有精確值均 表相應近似值「γ ( ^ - ,針對特定因素或量測所提供之所； 修飾）。 見為提供相應近似量測，適當時藉由「； 除非另外說明 或與上下文明顯抵觸 否則本文中針| 12 201033181 要素使用諸如「包含」、「具有」、「包括」或「含有」 之術語之本發明態樣的說明意欲證實本發明之類似態樣 「由彼或彼等特定要素組成」、「基本上由彼或彼等特定 要素組成」或「實質上包含彼或彼等特定要素」（例如除 非另外說明或與上下文明顯抵觸，否則本文描述包含特定 要素之組成物應瞭解亦描述由元素組成之组成物）。 實施例 Ο 分析方法 ]H NMR ^ i§ 經 Bruker Avance DRX500 儀在 500.13 MHz下記錄。二甲亞砜（99.8%D)用作溶劑，且將四甲基 矽烷（TMS )用作内部參考標準物。 使用差示掃描熱量測定法（D S C )量測溶點。設備為 TA-Instruments DSC-Q1000’ 其以 5Vmin 校準以得到熔點 作為初始值。將約2 mg樣品於鬆閉合盤中、在氮氣流下以 5 ° /min 加熱。 Q 用於估計脫水物質之溶劑/水含量之熱解重詈分；|：彳_ XJTGA)係使用 TA- Instruments TGA-Q500 進行。將 i_i〇 mg 樣品在開口盤中、在氮氣流下以1 〇。/min加熱。 2L光粉末繞射圖（XRPD )後經使用CuK α !輻射的 PANalytical X’Pert PRO X射線繞射儀量測。使用 X'celerator偵測器、在5-40 °之20範圍中、以反射方式量 測樣品。繞射數據以±0.1 (。2 0 )表示。 1^(2,4-二甲苯硫基）苯基1哌口丼-HBr之純唐徭推用梯度 逆相HPLC方法、應用Luna笨基己基管柱（150x4.6 mm、 13 201033181 # m粒度）來測定。移動相由純化水及用三氟乙酸酸化 之乙腈組成。流動速率1 ·〇 mL/rnin、管柱烘箱4(TC、注射 體積50 #L。使用226 nM之UV偵測定量峰面積。 趾係使用Varian Vista PRO ICP-OES (感應耦合電漿 原子反射光譜分析）來定量分析。波長：340.458 nm、342.122 nm、360.955 nm 〇 f施例1 :製備石-形式之1-(2.4-二甲茉硫基）苯基1哌a# -HBr，參艮 WO 2007/144005 夕實施例 4c 將49.5公克l-[2-(2,4-二曱苯硫基）-苯基]哌畊無色油 狀物溶解於500 mL乙酸乙酯中且添加18.5 mL 48 wt%之 HBr (水溶液）。此添加導致形成稠漿液，在室溫下攪拌隔 夜。過濾且真空脫水（50°C )隔夜，產生29.6公克呈白色 固體狀之產物（47%)。 NMR 符合結構。元素分析：56.86°/。C，7.3 5% N, 6.24% H(l:l 之鹽的理論值：56.99% C，7.3 9% N，6.11% H)。 實施例2 :特性化厶-形式之1-(2,4-二甲笨硫基）茉基1 哌姘-HBr，泉自.WO 2007/144005之實施例4d 如實施例1所製備之/5形式之氫溴酸鹽為結晶體 (XRPD)，參見圖1。其熔點為約23 1°C。其當曝露於高 相對濕度時吸收約0.6%之水且於水中之溶解度為1.2 mg/mL。 會施例L fl備1-(2,4-二甲笨硫基）笨基1哌讲-HBr里而 醇溶劍合物 加熱1-(2,4-二甲苯硫基）苯基]哌畊-HBr ( 25 g)於異丙 201033181 醇（250 mL)中之溶液，產生稠懸浮液，再添加異丙醇（25 mL )及水（25 mL )且將懸浮液加熱至回流得到溶液。將溶 液空白過濾、經冰浴冷卻且過濾。所得產物在5〇5>c下真空 脫水。 實施例~~生·特性化~~Li(2,4-二甲苯硫基基ι〇底讲.HBr 異丙醇溶f!丨合物 異丙醇溶劑合物（例如實施例3中所製備之異丙酵溶 劑合物）為結晶體（XRPEO ，參見圖2。TGA顯示在8(TC 緩慢開始脫去溶劑，且在12(rc完全脫去溶劑。重量損失經 量測達12.2%。DSC顯示對應於去溶劑化之吸熱。去溶劑化 之後’形成225 C炼融之無溶劑結晶鹽。所加熱樣品之xprd 顯示，此為α形式（對於α -形式之定義參見w〇 2007/144005 ) 。α -形式接著部分再結晶為在23〇χ：熔融之 形式，可能為冷-形式》TGA及DSC熱分析圖顯示於圖3 中 〇 ❿ 宜施例5 :繞土i 1-(2,4-二甲苯踹基）裟篡 用於此實施例中兩種方法之起始物質為含有化合物1 (4.8%)、化合物 2( 0.19%)及化合物 3 ( 0.18%)之 1-(2,4-'一甲本硫基）苯基]旅啡- HBr。 將1-(2,4-二甲苯硫基）苯基]旅啡_HBr( 33.1 Kg)於異 丙醇（412 L)與水（18 L)之混合物中加熱至回流。使溶 液冷卻至20°C且藉由過濾分離^(2，^二甲苯硫基）苯基]哌 畊之異丙醇溶劑合物且用異丙酵（82 L )洗滌。在回流下將 濕滤餅溶解於異丙醇（353 L)與水（17 L)之混合物中。 15 201033181 使溶液冷卻至20°C且藉由過濾分離i_(2,4-二甲苯硫基）苯 基]旅啡之異丙醇溶劑合物且用異丙醇（74 l )洗滌。在80 C將濕遽餅溶解於甲苯（132]L)與水（13 L)之混合物中 且空白過渡。自反應器中蒸餾出水及異丙醇（55L)，當餾 出物達1 021時停止蒸餾。接著添加水（7 l )且使溶液緩 慢冷卻至20。(：。藉由過濾分離二甲苯硫基）苯基]哌 啡-HBr ’用甲苯（77 L )洗滌濾餅且脫水。雜質含量如下： 化合物1小於0.05%，化合物2小於〇〇15%及化合物3小 於 0.05%。 為了比較，亦使用以下方法純化起始物質。將1 g l-(2,4-二曱苯硫基）苯基]哌畊_jjBr於甲苯（10 mL)中加熱 至回流。接著添加水（0.6 mL )且將溶液加熱至回流得到澄 清溶液。使此溶液冷卻至約2〇°c，接著經冰浴進一步冷卻。 藉由過渡分離1-(2,4-二甲苯硫基）苯基]哌畊·ΗΒγ，且於真空 烘箱中脫水得到（0.9 g)。 雜質含量如下：化合物1佔4%，化合物2佔0.15%及 化合物3佔0.14%。 實施例6 :純化—1^1·二甲茉葙某、芏某1畈崎-HRr 用於此實施例之1-(2,4-二甲苯硫基）苯基]哌畊HBr批 料含有化合物1 (0_5%)。 將114 kg HBr鹽於異丙醇（丨424 L)與水（64 L)之 混合物中加熱至回流。使溶液冷卻且藉由過濾分離^(2,^ 二甲苯硫基）苯基]哌畊-ΗΒγ異丙醇溶劑合物。在8〇。€下將 溶劑合物溶解於甲苯（513 L)與水（5〇 L)之混合物中且 201033181 空白過滤。蒸餾出水及異丙醇， ^ — 儿备餾出物達102°C時停止 蒸德。添加水（2 7 L)且估.、办、—a ,、 )且使溶液冷卻至2〇°C且藉由過渡分 離1-(2,4-二曱苯硫基）苯基]哌诽 田田w 个恭用甲笨洗滌濾餅。分 析最終產物顯示化合物i小於〇 J於U.05 /。，且XRDp數據證實獲 得冷-形式。 實施_例7 製造及純化1_ρ ,, _ α, γ r. u , n —T -查疏基）茉某1哌of -HBr 在氮氣氛圍下，在室溫下攪拌pddba2 (2u mg，〇 Μ? mm〇1)、BINAP ( 458 mg，Μ% 咖〇1)、第三 丁醇納（％ 〇 g)、派讲（27.5g)及甲苯（185mL)約3〇分鐘。向此混 合物中添加1-演-2-破苯（12 mL)及2,‘二甲基硫酚（i2 3 mL )且不加熱而擾拌反應混合物約6〇分鐘。接著在回流下 加熱反應混合物5小時，且接著添加水（7〇 mL )，隨後再 攪拌5分鐘’接著分離各相（大於6〇°c之溫度）。用氯化 鈉溶液洗滌甲苯相2次。向溫熱甲苯相中添加氫漠酸48% (16.2 g )’添加種晶（HBr /5 -形式）且使溶液冷卻。藉 由過濾分離1-(2,4-二曱苯硫基）苯基]哌畊_HBr ,且用甲笨 (160 mL)及水（190 mL)洗務濾餅。分析脫水之濾餅樣 品顯示0.64%化合物1及70 ppm Pd。濕濾餅於異丙醇（345 mL )中、在回流溫度下加熱且空白過濾熱溶液。使澄清溶 液冷卻至室溫以下，藉由過濾分離1-(2,4-二曱苯硫基）苯基] 哌畊-HBr之異丙醇溶劑合物’用異丙醇（40 mL )洗務且在 40°C下真空脫水。分析顯示化合物1 ( 0.05%)及2 ppm Pd。 將l-(2,4-二甲苯硫基）苯基]哌畊-HBr異丙醇溶劑合物 17 201033181 (19.5 g )、曱苯（100 mL )及水（5 mL)加熱至回流溫度， 且藉由蒸餾（23 mL)移除水及異丙醇。添加曱苯（23 mL) 且使溫度升尚至回流溫度’隨後添加水（1 〇 m L )且使溶液 冷卻至室溫。藉由過濾分離1-(2,4-二曱苯硫基）苯基]哌畊 -HBr ’用冷曱苯（70 mL )洗滌且在5〇。〇下真空脫水。分析 顯示低於0.05%之化合物1及1 ppm之pd。XRDP數據證實 獲得/3 -形式。 f施例8 :製造及純化1-(2,4-二甲茉硫基）笨基1旅_ 〇 將 1000 g Pddba2、3600-4600 g BINAP、270-310 kg 第 三丁醇鈉、360-420 kg哌畊及1300-1500 L甲苯饋入反應器 中’且攪拌混合物至少30分鐘。添加210-214 kg 1-溴-2-峨苯及99.5-100.5 kg 2,4-二甲基硫酚且將所得混合物在低 於25°C下攪拌至少60分鐘。使溫度升高至80-951：歷時至 少13小時。使混合物冷卻，添加1〇〇〇_12〇〇 l水，且分離 各相。用總計1 070-1 140 kg約150/〇之NaCl洗滌甲苯相若干 次。添加126-128 kg HBr 48%及40-46 L水，且加熱混合物 ❹ 直至獲得完全澄清之溶液。藉由冷卻獲得標題化合物之粗 晶體。藉由過濾分離晶體’且用10004200 [甲苯及400-700 L水洗務晶體。將濾餅溶解於3〇63_3112 [異丙醇中且空白 過濾所得溶液。加熱溶液，且蒸餾出247〇_2964 L，接著添 加145 7-15 07 L異丙醇。藉由加熱獲得完全溶解，且藉由冷 卻獲得異丙醇溶劑合物之晶體。藉由過濾分離晶體，隨後 用865-914 L異丙醇洗丨條。 18 201033181 將200 kg l-(2,4-二甲苯硫基）苯基]哌畊_HBr異丙醇々 劑合物添加至980-1020 L甲苯及48_52 L水中。加熱溶ς 晶體且空白過濾該溶液。蒸餾溶液直至蒸氣溫度高於 l〇2°C，且添加與餾出物之體積等量之甲苯。再添加48 52 l 水且加熱液體直至完全溶解。藉由冷卻及接種使卢形式之 1-(2,4-二甲苯硫基）苯基]哌畊-HBr結晶。 【圖式簡單說明】 圖1 :心形式之1-[2-(2,4-二甲苯硫基）苯基]哌畊-HBr ❹Similar as if not considered to cover singular and plural. For example, unless otherwise stated, it should be understood that the term "the compound" is a compound of the month or a specific description. ^Alternatively, otherwise all the exact values provided herein are given the corresponding approximation "γ ( ^ - , for the specific factors or measurements provided; modification). See to provide the corresponding approximation, as appropriate by "; Unless otherwise stated or clearly contradicted by context, the description herein refers to aspects of the invention in which terms such as "including," "having," "including," "Consisting of the other elements" or "substantially consisting of the other elements" or "substantially including one or the other specific elements" (eg, unless otherwise stated or clearly contradicted by context) The composition of a particular element should be understood to also describe the composition of the elements). EXAMPLES Ο Analytical method] H NMR ^ i§ Recorded at 500.13 MHz on a Bruker Avance DRX500 instrument. Dimethyl sulfoxide (99.8% D) was used as a solvent, and tetramethyl decane (TMS) was used as an internal reference standard. The melting point was measured using differential scanning calorimetry (D S C ). The apparatus was a TA-Instruments DSC-Q1000' which was calibrated at 5 Vmin to obtain the melting point as an initial value. Approximately 2 mg of the sample was heated in a loose closed pan at 5 ° / min under a stream of nitrogen. Q The pyrolysis weight fraction used to estimate the solvent/water content of the dehydrated material; |:彳_XJTGA) was performed using a TA- Instruments TGA-Q500. The i_i〇 mg sample was placed in an open pan at 1 Torr under a stream of nitrogen. /min heating. The 2L light powder diffraction pattern (XRPD) was measured by a PANalytical X'Pert PRO X-ray diffractometer using CuK α ! radiation. Samples were measured by reflection using an X'celerator detector in the range of 5-40 °20. The diffraction data is expressed as ±0.1 (.20). 1^(2,4-Dimethylthio)phenyl 1 piperidine-HBr pure gradient ruthenium gradient gradient reverse phase HPLC method, application Luna stupid base column (150x4.6 mm, 13 201033181 # m particle size ) to determine. The mobile phase consisted of purified water and acetonitrile acidified with trifluoroacetic acid. Flow rate 1 ·〇mL/rnin, column oven 4 (TC, injection volume 50 #L. Use 226 nM UV to detect quantitative peak area. Toe system uses Varian Vista PRO ICP-OES (inductively coupled plasma atomic reflectance spectroscopy) Analytical) for quantitative analysis. Wavelength: 340.458 nm, 342.122 nm, 360.955 nm 施f Example 1: Preparation of stone-form 1-(2.4-dimethylumthio)phenyl 1 pipea#-HBr, ginseng WO 2007 /144005 例 Example 4c 49.5 g of 1-[2-(2,4-diphenylsulfanyl)-phenyl] piped colorless oil was dissolved in 500 mL of ethyl acetate and added 18.5 mL of 48 wt% HBr (aq). This addition resulted in the formation of a thick syrup which was stirred overnight at room temperature, filtered and vacuum dried (50 ° C) overnight to yield 29.6 g of product (47%) as a white solid. Analysis: 56.86 ° /. C, 7.3 5% N, 6.24% H (the theoretical value of the salt of 1:1: 56.99% C, 7.3 9% N, 6.11% H). Example 2: Characterization 厶-form 1-(2,4-Dimethylthiomethyl)methyl 1 Piperazine-HBr, Example 4d of WO 2007/144005. The hydrobromide salt of the form 5 prepared as in Example 1 is a crystal ( XRPD), see 1. Its melting point is about 23 ° C. It absorbs about 0.6% of water when exposed to high relative humidity and has a solubility in water of 1.2 mg / mL. Example L fl is prepared 1- (2, 4- A thiol thiol) phenyl 1 piper-HBr and an alcohol-soluble saponin heated 1-(2,4-dimethylphenylthio)phenyl]piped-HBr (25 g) in isopropyl 201033181 alcohol (250 The solution in mL) gave a thick suspension, then isopropanol (25 mL) and water (25 mL) were added and the suspension was heated to reflux to give a solution. The solution was filtered in vacuo, cooled in ice bath and filtered. Vacuum dehydration at 5 〇 5 > c. Example ~ ~ Health · characterization ~ ~ Li (2,4-dimethylbenzene thio 〇 讲 .. HBr isopropanol dissolved f! bismuth isopropanol solvent The compound (such as the isopropyl solvate prepared in Example 3) is a crystalline form (XRPEO, see Figure 2. TGA is shown at 8 (TC slowly starts to remove solvent, and at 12 (rc completely removes solvent. Weight The loss was measured by 12.2%. DSC showed an endotherm corresponding to desolvation. After desolvation, 'forms a solvent-free crystalline salt of 225 C smelting. The xprd of the heated sample shows that this is the alpha form (for α-form) For the definition of formula, see w〇2007/144005. The α-form is then partially recrystallized to 23〇χ: the form of melting, possibly cold-form. The TGA and DSC thermograms are shown in Figure 3. 5: the soil i 1-(2,4-dimethylphenyl) ruthenium. The starting materials for the two methods in this example are compound 1 (4.8%), compound 2 (0.19%) and compound 3. (0.18%) of 1-(2,4-'-monomethylthio)phenyl]benzol-HBr. 1-(2,4-Dimethylthio)phenyl]benphine-HBr (33.1 Kg) was heated to reflux in a mixture of isopropyl alcohol (412 L) and water (18 L). The solution was cooled to 20 ° C and the isopropyl alcohol solvate of (2,^-dimethylthio)phenyl]piper was isolated by filtration and washed with isopropyl alcohol (82 L). The wet cake was dissolved in a mixture of isopropanol (353 L) and water (17 L) under reflux. 15 201033181 The solution was cooled to 20 ° C and the isopropanol solvate of i-(2,4-dimethylphenyl)phenyl]benzolone was isolated by filtration and washed with isopropanol (74 l). The wet cake was dissolved in a mixture of toluene (132) L) and water (13 L) at 80 C with a blank transition. Water and isopropanol (55 L) were distilled from the reactor, and distillation was stopped when the distillate reached 1,021. Water (7 l ) was then added and the solution was slowly cooled to 20. (: Separation of xylylthio) by filtration] Phenyl] piperidine-HBr 'The filter cake was washed with toluene (77 L) and dehydrated. The impurity content is as follows: Compound 1 is less than 0.05%, Compound 2 is less than 〇〇15%, and Compound 3 is less than 0.05%. For comparison, the starting materials were also purified using the following method. 1 g of 1-(2,4-diphenylthio)phenyl]pitricin-jjBr was heated to reflux in toluene (10 mL). Water (0.6 mL) was then added and the solution was heated to reflux to give a clear solution. The solution was allowed to cool to about 2 ° C and then further cooled in an ice bath. 1-(2,4-Dimethylthio)phenyl]piperidine·ΗΒγ was separated by a transition and dehydrated in a vacuum oven to obtain (0.9 g). The impurity content was as follows: Compound 1 accounted for 4%, Compound 2 accounted for 0.15%, and Compound 3 accounted for 0.14%. Example 6: Purification - 1^1·Dimethyl hydrazine, 芏一1畈崎-HRr The 1-(2,4-dimethylthio)phenyl]pitricon HBr batch used in this example contained Compound 1 (0_5%). 114 kg of HBr salt was heated to reflux in a mixture of isopropanol (丨 424 L) and water (64 L). The solution was allowed to cool and the ?(2,^-dimethylthio)phenyl]pitricol-ΗΒγ-isopropanol solvate was isolated by filtration. At 8 〇. The solvate was dissolved in a mixture of toluene (513 L) and water (5 〇 L) with a vacuum filtration of 201033181. Distilled water and isopropanol, ^ - Stop steaming when the distillate reaches 102 °C. Add water (2 7 L) and estimate, do, -a, , and cool the solution to 2 ° C and separate 1 - (2,4-diphenylthio)phenyl]piperidin by transition Tian Tian w Gong used a stupid washing filter cake. Analysis of the final product showed that compound i was less than 〇 J at U.05 /. And the XRDp data confirmed that cold-form was obtained. Example _ Example 7 Manufacture and purification of 1_ρ ,, _ α, γ r. u , n — T — 查 基 ) 茉 茉 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌 哌? mm〇1), BINAP (458 mg, Μ% curry 1), third butanol (% 〇g), transcript (27.5 g) and toluene (185 mL) for about 3 minutes. To this mixture was added 1-act-2-benzene (12 mL) and 2, dimethyl thiophenol (i2 3 mL) and the mixture was stirred without stirring for about 6 min. The reaction mixture was then heated under reflux for 5 hours, and then water (7 mL) was added, followed by stirring for another 5 minutes' followed by separation of the phases (temperature greater than 6 °C). The toluene phase was washed twice with a sodium chloride solution. To the warm toluene phase, 48% (16.2 g) of hydrogen desert acid was added to add seed crystals (HBr/5-form) and the solution was allowed to cool. The 1-(2,4-diphenylthio)phenyl]piperidine-HBr was isolated by filtration, and the filter cake was washed with EtOAc (160 mL) and water (190 mL). Analysis of the dehydrated filter cake sample showed 0.64% Compound 1 and 70 ppm Pd. The wet cake was heated in isopropanol (345 mL) at reflux temperature and the hot solution was filtered. The clear solution was cooled to below room temperature and the 1-(2,4-diphenylthio)phenyl]piperidine-HBr isopropanol solvate was isolated by filtration and washed with isopropanol (40 mL). And vacuum dehydration at 40 ° C. Analysis showed Compound 1 (0.05%) and 2 ppm Pd. Heating l-(2,4-dimethylphenyl)phenyl]pitricon-HBr isopropanol solvate 17 201033181 (19.5 g), toluene (100 mL) and water (5 mL) to reflux temperature. Water and isopropanol were removed by distillation (23 mL). Toluene (23 mL) was added and the temperature was raised to reflux temperature. Then water (1 〇 m L ) was added and the solution was allowed to cool to room temperature. The 1-(2,4-diphenylthio)phenyl]piperidine-HBr' was isolated by filtration and washed with cold benzene (70 mL) at 5 Torr. Underarm vacuum dehydration. Analysis showed less than 0.05% of Compound 1 and 1 ppm of pd. The XRDP data confirms the /3 - form. f Example 8: Manufacture and purification of 1-(2,4-dimethylumylthio) stupid 1 brigade _ 〇 1000 g Pddba2, 3600-4600 g BINAP, 270-310 kg sodium butoxide, 360- 420 kg of piper and 1300-1500 L of toluene were fed into the reactor' and the mixture was stirred for at least 30 minutes. 210-214 kg of 1-bromo-2-indenebenzene and 99.5-100.5 kg of 2,4-dimethylthiophenol were added and the resulting mixture was stirred at less than 25 ° C for at least 60 minutes. Increase the temperature to 80-951: for at least 13 hours. The mixture was allowed to cool, 1 〇〇〇 12 Torr of water was added, and the phases were separated. The toluene phase was washed several times with a total of 1 070-1 140 kg of about 150/inch NaCl. 126-128 kg HBr 48% and 40-46 L water were added and the mixture was heated until a completely clear solution was obtained. The crude crystal of the title compound was obtained by cooling. The crystals were separated by filtration and the crystals were washed with 10004200 [toluene and 400-700 L of water. The filter cake was dissolved in 3〇63_3112 [isopropanol and the resulting solution was filtered. The solution was heated and 247 〇 2 964 L was distilled off, followed by the addition of 145 7-15 07 L of isopropanol. The complete dissolution was obtained by heating, and the crystal of the isopropanol solvate was obtained by cooling. The crystals were separated by filtration, and then the strips were washed with 865-914 L of isopropanol. 18 201033181 200 kg of l-(2,4-dimethylphenyl)phenyl]piperidine-HBr isopropoxide ruthenium complex was added to 980-1020 L of toluene and 48_52 L of water. The crystals were dissolved and the solution was filtered in vacuo. The solution was distilled until the vapor temperature was higher than 10 ° C, and an equal amount of toluene was added to the volume of the distillate. Add another 48 52 l of water and heat the liquid until completely dissolved. The form of 1-(2,4-dimethylphenylthio)phenyl]piped-HBr was crystallized by cooling and inoculation. [Simple diagram of the figure] Figure 1: 1-[2-(2,4-Dimethylthio)phenyl]piped-HBr 心 in heart form

之 XRPDXRPD

圖2:卜[2-(2,4-二甲苯硫基）笨基]哌畊-HBr異丙醇溶 劑合物之XRPD 圖3: 1-[2-(2,4-二甲苯硫基）苯基]派啡- HBr異丙醇溶 劑合物之TGA及DSC熱分析圖 圖4: ι_[2-(2,4-二甲基_苯硫基）_苯基]-4-(2-娘讲-1-基- 苯基）-娘畊 圖5: ι_[2-(5-氯-2,4_二曱基_苯硫基）笨基]0辰讲 ◎圖6:卜[2-(2,6-二甲苯硫基）笨基]派畊 【主要元件符號說明】 無 19Figure 2: XRPD of a solvate of 2-[2,4-dimethylthio)phenyl]HBr isopropanol Figure 3: 1-[2-(2,4-Dimethylthio) TGA and DSC thermal analysis of phenyl]pyrone-HBr isopropanol solvate Figure 4: ι_[2-(2,4-dimethyl-phenylthio)phenyl]-4-(2- Niangyan-1-yl-phenyl)-mother farming Figure 5: ι_[2-(5-chloro-2,4_didecyl-phenylthio) stupid base] 0 Chen speaks ◎ Figure 6: Bu [2 -(2,6-Dimethylthio) stupid base] sent to cultivate [main symbol description] No 19

Claims (1)

201033181 七、申請專利範圍： 1·—種製造1-[2-(2,4-二甲苯硫基）苯基]旅啡或其醫藥 學上可接受之鹽之方法’該方法包括藉由將二甲 苯硫基）苯基]哌啡-HBr鹽溶解於包含超過65% ( v/v )之異 丙醇之溶劑中獲得溶液之步驟。 2. 如申請專利範圍第1項之方法，其中該醫藥學上可接 受之鹽為HBr鹽。 3. 如申請專利範圍第2項之方法，其中該醫藥學上可接 受之鹽為/3-形式之HBr鹽。 4. 如申請專利範圍第1項至第3項中任一項之方法，其 中該溶劑包含超過8 5 % ( v/v )之異丙醇。 5. 如申請專利範圍第1項至第4項中任一項之方法，該 方法包含使1-[2-(2,4-二甲苯硫基）苯基]派畊-HBr異丙醇溶 劑合物自該溶液中沈澱之後續步驟。 6·—種製造1-[2-(2,4-二甲苯硫基）苯基]哌畊或其醫藥 學上可接受之鹽之方法，該方法包含使1-[2-(2,4-二曱苯硫 基）苯基]哌畊-HBr異丙醇溶劑合物自包含超過65% ( v/v ) 之異丙醇的溶劑中沈澱之步驟。 7. 如申請專利範圍第6項之方法，其中該醫藥學上可接 受之鹽為HBr鹽。 8. 如申請專利範圍第7項之方法，其中該醫藥學上可接 受之鹽為/3-形式之HBr鹽。 9. 如申請專利範圍第6項至第8項中任一項之方法’其 中該溶劑包含超過85% ( v/v)之異丙醇。 201033181 10.一 種製造 l-[2-(2 4 -田 # 泣 is 學上可接受之鹽之方法二：本基)本基]料或其醫藥 — 該方法包含將1-[2-(2,4-二甲苯硫 土 )：基]哌畊HBr異丙醇溶劑合物溶解於不形成溶劑合物 之溶劑中、隨後使1_[2 殿之步驟。 ’ ·—甲U)本基㈣撒沈 11.如申請專利範圍箆1n 固弟10項之方法，其中該不形成溶劑 曱 甲醇、乙醇、丙 〇 合物之溶劑係選自水、THF 酮及甲苯及其混合物 M12·如巾請專利範圍第11項之方法，其中該不形成溶劑 σ物之溶劑包含超過80〇/〇之甲苯。 13·如申請專利範圍第1〇項之方法，其中該醫藥學上可 接受之鹽為HBr鹽。 14. 如申請專利範圍第13項之方法，其中該醫藥學上可 接又之鹽為形式之HBr鹽。 15. 如申請專利範圍帛！項之方法’該方法包括 驟： a) 藉由將1-[2·(2,4_二甲苯硫基）苯基]哌畊4&溶 解於包含超過65% ( ν/ν )之異丙醇的溶劑中獲得溶液. b) 使1-[2-(2,4-二甲苯硫基）苯基；|哌畊_HBr異丙醇 溶劑合物自該所得溶液中沈澱； c) 將1-[2-(2,4-二曱苯硫基）苯基]η辰啡_HBr異丙醇 溶劑合物溶解於不形成溶劑合物之溶劑中；及 d) 使1-[2-(2,4-二曱苯硫基）苯基]派啡_jjBr自c) 所得之溶液中沈澱。 21 201033181 16·如申明專利範圍第15項之方法，其中步驟a)中之 該溶劑包含超過8 5 0/广 、 /〇(v/v)之異丙醇，且步驟c)中之該 不形成溶劑合物之溶劑包含超過80% (v/v)之甲苯。 17·如申請專利範圍第15項或第16項之方法，其中該 醫藥學上可接受之鹽為HBr鹽。 18. 如申請專利範圍第17項之方法，其中該醫藥學上可 接受之鹽為沒-形式之HBr鹽。 19. —種自固體^[2-(2,4-二曱苯硫基）苯基]哌畊·ΗΒγ 中或自1-[2-(2,4-二甲苯硫基）苯基]略畊_HBr之溶液中移除 ◎ 戒減少雜質的方法，該方法包括以下步驟： a )使包含超過65 % ( v/v )之異丙醇的溶劑與固體 1-[2-(2,4-二甲苯硫基）苯基]〇底畊_HBr或與1-[2-(2,4-二 甲苯硫基）苯基]哌畊-HBr之溶液混合以獲得ι_[2-(2,4-二甲苯硫基）苯基]哌畊-HBr之溶液；及 b) 冷卻該所得溶液以使1-[2-(2,4_二甲苯硫基）苯基] 哌畊-HBr異丙醇溶劑合物沈澱； c) 將1-[2-(2,4-二甲苯硫基）苯基]哌畊-HBr異丙醇 ◎ 溶劑合物溶解於不形成溶劑合物之溶劑中；及 d) 使1-[2-(2,4-二甲笨硫基）苯基]哌畊-HBr自步驟 c)所得之溶液中沈澱。 20. 如申請專利範圍第19項之方法，其中該雜質係選自 卜[2-(2,4-二甲基-苯硫基苯基]-4_(2_α底口井-1 -基苯基）-0辰口井 或其鹽；1-[2-(5-氯-2,4-二曱基-苯硫基）苯基]哌畊或其鹽； 卜[2-(2,6-二甲苯硫基）苯基]派畊或其鹽 ;或纪。 22 201033181 21. —種液體溶液，其包含1-(2,4-二曱苯硫基）苯基]哌口井 於超過65% ( v/v)之異丙醇中。 22. —種化合物，其為1-[2-(2,4-二曱苯硫基）苯基]哌畊 -HBr異丙醇溶劑合物。 23. 如申請專利範圍第22項之化合物，該化合物具有位 於約 6.44、8.13、8.77、10.41 ( 02θ )之 XRPD 反射。 24. 如申請專利範圍第23項之化合物，其具有如圖2所 示之XRPD。 〇 八、圖式： (如次頁）201033181 VII. Scope of application for patents: 1. A method for producing 1-[2-(2,4-dimethylphenyl)phenyl]benzine or a pharmaceutically acceptable salt thereof] The step of dissolving the xylylthio)phenyl]pipephin-HBr salt in a solvent containing more than 65% (v/v) of isopropanol to obtain a solution. 2. The method of claim 1, wherein the pharmaceutically acceptable salt is HBr salt. 3. The method of claim 2, wherein the pharmaceutically acceptable salt is a /3-form HBr salt. 4. The method of any one of claims 1 to 3, wherein the solvent comprises more than 85 % (v/v) of isopropanol. 5. The method of any one of claims 1 to 4, which comprises the step of 1-[2-(2,4-dimethylphenyl)phenyl]-p-HBr isopropanol solvent The subsequent step of precipitation of the compound from the solution. A method for producing 1-[2-(2,4-dimethylphenyl)phenyl]piramine or a pharmaceutically acceptable salt thereof, the method comprising the step of 1-[2-(2,4) The step of precipitating from a solvent containing more than 65% (v/v) of isopropanol of di-phenylsulfonyl)phenyl]pitricon-HBr isopropanol solvate. 7. The method of claim 6, wherein the pharmaceutically acceptable salt is HBr salt. 8. The method of claim 7, wherein the pharmaceutically acceptable salt is a /3-form HBr salt. 9. The method of any one of clauses 6 to 8 wherein the solvent comprises more than 85% (v/v) of isopropanol. 201033181 10. A method for producing l-[2-(2 4 -田# weis is a salt of acceptable salt): a base material] or a medicament thereof - the method comprises 1-[2-(2 , 4-xylene sulphate: base] Piper HBr isopropanol solvate is dissolved in a solvent which does not form a solvate, and then the step of 1_[2 殿. ' · - A U) base (four) sprinkle 11. As claimed in the scope of patent application 箆 1n Gu Di 10, wherein the solvent is not formed, the solvent of methanol, ethanol, propylene complex is selected from water, THF ketone and Toluene and its mixture M12. The method of claim 11, wherein the solvent which does not form the solvent σ comprises more than 80 〇/〇 of toluene. 13. The method of claim 1, wherein the pharmaceutically acceptable salt is a HBr salt. 14. The method of claim 13, wherein the pharmaceutically acceptable salt is a form of HBr salt. 15. If you apply for a patent scope! The method of the invention comprises the steps of: a) dissolving 1-[2·(2,4-dimethylthio)phenyl]piped 4& dissolved in isopropyl containing more than 65% (v/v) Obtaining a solution in a solvent of an alcohol. b) allowing 1-[2-(2,4-dimethylphenyl)phenyl;|piperidin-HBr isopropanol solvate to precipitate from the resulting solution; c) -[2-(2,4-Diphenylthio)phenyl]n henyl _HBr isopropanol solvate is dissolved in a solvent which does not form a solvate; and d) makes 1-[2-( 2,4-Diindolylthio)phenyl]pyrone _jjBr was precipitated from the resulting solution. The method of claim 15, wherein the solvent in step a) comprises more than 850 / Å, / 〇 (v / v) of isopropanol, and in step c) The solvent forming the solvate contains more than 80% (v/v) toluene. 17. The method of claim 15 or claim 16, wherein the pharmaceutically acceptable salt is a HBr salt. 18. The method of claim 17, wherein the pharmaceutically acceptable salt is a non-form of the HBr salt. 19. —from solid ^[2-(2,4-diphenylthio)phenyl]piped·ΗΒγ or from 1-[2-(2,4-dimethylphenyl)phenyl] A method of removing ◎ or reducing impurities in a solution of cultivating _HBr, the method comprising the steps of: a) making a solvent containing more than 65% (v/v) of isopropanol with solid 1-[2-(2,4) -xylthio)phenyl]phosphonium _HBr or a solution of 1-[2-(2,4-dimethylphenylthio)phenyl]piped-HBr to obtain ι_[2-(2, a solution of 4-dimethylthio)phenyl]pitricin-HBr; and b) cooling the resulting solution to give 1-[2-(2,4-dimethylsulfinyl)phenyl]piperidin-HBr isopropyl Alcohol solvate precipitation; c) dissolving 1-[2-(2,4-dimethylphenyl)phenyl]pitricon-HBr isopropanol solvate in a solvent which does not form a solvate; d) 1-[2-(2,4-Dimethylphenylthio)phenyl]pitricin-HBr is precipitated from the solution obtained in step c). 20. The method of claim 19, wherein the impurity is selected from the group consisting of [2-(2,4-dimethyl-phenylthiophenyl]-4_(2_α bottom well-1-1-ylphenyl) )-0 Chenkou or its salt; 1-[2-(5-chloro-2,4-didecyl-phenylthio)phenyl] piped or its salt; Bu [2-(2,6-II) Toluene-thiophenyl)phenyl] or its salt; or. 22 201033181 21. A liquid solution comprising 1-(2,4-diphenylthio)phenyl]piperazine in more than 65% (v/v) in isopropanol 22. A compound which is 1-[2-(2,4-diphenylthio)phenyl]pitricon-HBr isopropanol solvate. As claimed in claim 22, the compound has an XRPD reflection at about 6.44, 8.13, 8.77, 10.41 (02θ). 24. A compound according to claim 23, which has the structure shown in Figure 2. XRPD. 〇8, schema: (such as the next page) 23twenty three